Case control studies suggest that the e4 allele for APOE accounts for many cases of late-onset AD and that e4 homozygotes have an especially high risk of the disorder. Patients with AD have progressive declines in PET measurements of posterior cingulate, parietal, temporal, and prefrontal glucose metabolism, MRI measurements of hippocampal volume, and cognitive function. In this longitudinal study, PET, MRI, and a neuropsychological test battery will be used to characterize and compare declines in regional brain function, regional brain morphology, and performance prior to the onset of dementia in persons at high risk for AD. APOE genotypes will be characterized in volunteers 50-65 years of age who report a family history of AD. Every two years, neurologic and psychiatric evaluations, quantitative PET measurements of the cerebral metabolic rate for glucose, a T1-weighted volumetric MRI, and a battery of neuropsychological tests will be used to study 40 e4 homozygotes, 40 e4 heterozygotes, and 80 e4 non-carriers who are matched for gender, age, and educational level. Advanced image-analysis techniques will be used to characterize progressive declines in regional brain measurements prior to the onset of dementia in the e4 carriers and test the hypothesis that the rates of decline are directly related to e4 gene dose; additional analyses will establish which pathological chances best predict the onset of dementia. The research strategy described in this proposal provides a foundation for characterizing the neurophysiological, neuroanatomical, and cognitive changes associated with the course of AD and normal aging determining how variants of the APOE allele accelerate or retard these changes, and identifying treatments which could minimize their progression. If, as postulated, e4 carriers have progressive declines in brain function and morphology prior to the onset of dementia, this strategy will provide a relatively rapid way of testing treatments to prevent AD.